Month: December 2018

The major news was the report of the birth of the first children genetically modified as embryos. I report on that separately here.

The question of whether those who receive a genetic diagnosis have a duty to tell their family members is working its way through the UK courts. A man who received a genetic diagnosis of Huntington’s asked the hospital not to tell his daughter, who was pregnant at the time, because he feared she would abort the baby. The daughter has since been found to have the genetic variant associated with Huntington’s is now suing the hospital. Bioethicist Anna Middleton told the Guardian “This could really change the way we do medicine, because it is about the duty that doctors have to share genetic test results with relatives and whether the duty exists in law.”

PsychENCODE, a large consortium looking at functional genomics in over 2000 developing and adult brains, has published 10 papers. To focus on one paper, they found that differences in gene expression between individuals are mostly explained by differences in fractions of cell types, and that some disorders and aging are associated with changes in these proportions. For schizophrenia, they found 321 genes associated with GWAS loci, and then did some fancy machine learning to predict phenotype from genotypes and from expression. This model did much better than a genotype polygenic score alone, and still did better when the expression data was imputed (i.e. not actually experimentally measured), “highlighting the value of having just a small amount of transcriptome data for disease prediction.”

Large study of the genetics of ADHD finds reproducible loci. A polygenic score predicts 5.5% of the variance (for an odds ratio of 1.56). The study presents evidence that ADHD should be considered the end of a distribution: “Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.”

A much smaller fraction of developmental disorders (DDs) are explained by recessive variation in protein-coding genes than previously thought: ~3.6% in non-consanguineous populations, compared to 31% in consanguineous populations. Compare to 50% of DDs caused by de novo mutations. This work, from Hilary Martin et al appearing in Science, is based on a burden analysis approach in over 6000 exomes from the Deciphering Developmental Disorders study. “The high proportion of unexplained patients even amongst those with affected siblings or high consanguinity suggests that future studies should investigate a wide range of modes of inheritance including oligogenic and polygenic inheritance as well as noncoding recessive variants.”

“Just thinking you have poor endurance genes changes your body” – individuals were told a test had revealed they had one or another version of the gene CREB1, which affects how easily one tires, and were then set to run on a treadmill. Those who were told they had the version would meant they would tire more easily did indeed tire more easily. In fact, the participants had been randomized. Likewise for FTO, which can affect how full you feel, participants who were told they had the “less hungry” version of the gene reported feeling less hungry, and had higher levels of a hormone associated with feeling full. This would be a type of placebo effect for genetic information: “The results suggest that if a person just thinks they are at high risk for, say, obesity, it could change their physiology in a way that makes them more prone to the condition, Turnwald says.” (Paper here). “If simply conveying genetic risk information can alter actual risk, clinicians and ethicists should wrestle with appropriate thresholds for when revealing genetic risk is warranted.”

Calico and Ancestry.com have teamed up to show that longevity is <10% genetic. Using a single pedigree of over 400 million individuals, they were able to show that previous estimates (about 15-30%) overestimated genetic inheritance because they were confounded by non-genetic inheritance showing up via the effects of assortative mating.

We’ve known for a long time that there is a lot of undiscovered genetic diversity in African populations, and that use of the reference genome is rife with problems. Sequencing of 910 African genomes has showed just how large the problem is: at least 10% of reads failed to align to the reference genome, but were alignable to constructed pan-African contigs.

Mendelian Randomization is the idea that because genetics at birth is randomized and not altered by environmental confounders, considering some gene X, one can see whether gene X is subject to Loss or Gain of Function variants in the disease of interest. If it is, then Gene X is s good drug candidate – many high cost drug trials could have been avoided if MR had been performed. The technique can also be used to distinguish between correlation and causation, for example in showing that the correlation between obesity and depression is at least partially explained by obesity causing depression (depression odds ratio of 1.18 for 1 SD higher genetic risk score for high BMI). There are many improvements to the most basic MR model, see e.g. correcting for genetic correlations with shared etiology.

A study has shown that over 30% of patients had their variants reclassified within a five year time period. “The findings of this study suggest that pediatric patients with epilepsy and previous genomic test results should have their test results reinterpreted at least every 2 years and before further genetic testing.”

More calls for a universal DNA database for use in forensics: “if correctly implemented, a universal database would likely be more productive and less discriminatory than our current system, without compromising as much privacy.”

The UN’s Convention on Biological Diversity considered, and rejected, a ban on gene drives. Both those working on gene drive technology and those campaigning against it called the result a win. They state the need for informed consent, but it is not clear what this means: “who gets to decide when the African people have consented — and how unanimous a decision you need when millions of lives are on the line”

In April 2018 the FDA issued guidance on the use of databases in genomic testing. Applying that guidance, they have approved use of ClinGen’s Expert Curated Human Genetic Data as clinical evidence in approval submissions for tests. The data covers over 10,000 variants (ClinVar review status (“reviewed by expert panel”or “practice guideline”).

I first learnt about Lulu and Nana by watching the video that Chinese scientist He Jiankiu published explaining why he had edited embryos leading to the births of the first genetically modified babies. This is strongly recommended viewing. You can read the story, as broken by the AP, here. His claims have yet to be verified.

It was anticipated that the first International Summit on Human Gene Editing, held three years ago, would result in a consensus statement calling for a moratorium on genetically modified babies. There was no call for a moratorium. Since then, others have failed to call for a moratorium. Including the US’s National Academies report (which I covered here) which instead produced a checklist for when editing could be performed (p132), and the UK’s Nuffield Council report.

There has been much criticism of He, for example Oxford’s Julian Savulescu, famous for arguing that we have a moral imperative to have the best children possible, described the work as “monstrous”; Penn’s Dr Kiran Musunuru described it as “unconscionable” (link). These voices included Chinese: Qiu Renzong, bioethicist and emeritus professor at the Chinese Academy of Social Science in Beijing, stated that the work was clearly not ethical, and a fraud (link).

While most have strongly condemned He’s work, some have taken a less accusatory stance. At the summit, Dr. George Daley, dean of Harvard Medical School, characterized He’s work as a “misstep” and argues “It is time to move forward from [debates about] ethical permissibility to outline the path to clinical translation … in order to bring this technology forward.” (link). George Church states “I feel an obligation to be balanced.”, calling the criticisms of He bullying.

Should the scientific community have acted differently? David Baltimore, the convener of the Second Summit, (reported by STAT) states that “I think there has been a failure of self-regulation by the scientific community because of the lack of transparency.” Scott Gottlieb, FDA Commissioner, goes further and says that the scientific community should not have given He a platform to self promote his work. “The response from the scientific community has been far too slow and far too tepid, and the credibility of the community to self-police has already been damaged… Governments will now have to react, and that reaction may have to take consideration of the fact that the scientific community failed to convincingly assert, in this case, that certain conduct must simply be judged as over the line” (reported in BioCentury). The work would have been illegal in the US. It also likely contravened Chinese laws (link). Lawyer Glenn Cohen questions that there could be a complicit scientific community, “it seems to me that the community is acting exactly as it should when one of its members breaks the covenant” (link).

The details of the research help highlight some open ethical issues. The aim of this research was to disable the CCR5 gene, a mutation that some people (though not Han Chinese) naturally have that is protective against HIV infection. The choice seems motivated to be a CRISPR first, rather than a pressing therapeutic need. Disabling a gene is much easier than precisely tweaking a “broken” gene to be functional. The desire for fame, to have a first, was a clear motivating factor for the research: the team wrote in their submitted ethics statement “In this ever more competitive global pursuit of applications for gene editing, we hope to be a stand-out”. Potential parents were only eligible for the study if the father had HIV. Infertile women are not eligible for IVF if their partner has HIV (link). The research is thus particularly question worthy as it a) blurred the lines between research, which is supposed to recruit individuals whose main aim is to contribute to scientific knowledge, and clinical application, where direct benefit is expected, b) edited healthy embryos, rather than seeking to “fix” those who would otherwise go on to develop a serious condition, c) individuals with the introduced edit have a higher chance of infection with the West Nile virus, and a higher chance of dying from influenza; as a protective mutation, d) the edit blurs the enhancement/therapy line, e) one of the embryos was known heterozygous (and hence would not have had the protective benefits) pre-implantation; whether the prospective parents could give true informed consent has been questioned. For the very real risk of off target effects, the consent form stated that “the project team is not responsible for the risk.” The case highlights just how ambiguous language is: An item on NASAM’s checklist was that editing be done for an “unmet” medical need. As Church points out, there is no cure or vaccine for HIV. On the other hand, HIV is both preventable and treatable.

What happens next? There are decisions ahead for any editor who receives the work to review. Francis Collins, who heads the NIH, has called for a “binding international consensus”. An editorial in Nature calls for a global registry of work genetically modifying human embryos. Carl Zimmer, writing in the New York Times, draws the parallel to babies born via mitochondrial replacement therapy, and the example of how the UK has made this legal within a highly regulated environment. Throughout this debacle, two reference cases have been given. The first is to Louise Brown, the first baby born by IVF. In the years around her birth, public opinion changed from being opposed to interfering with nature in this way, to being supportive of IVF (see Table 2 here). The second is to Jesse Gelsinger, who died in 1999 after receiving an experimental gene therapy. His death seems largely creditable to hastiness around excitement of a new technology. As George Church states, it is too early to tell whether Lulu and Nana will be Louise Browns or Jesse Gelsingers. But note that, post Jesse’s death, gene therapy is once again being pursued with gusto.

Why China? While international science incentives “firsts”, this may be acutely felt in China. As Jing-Bao Nie argues, “China’s science schemes have much to do with the developing mentality that ethics is merely secondary and instrumental for cutting-edge scientific investigation and technological invention”. Additionally, Chinese society places less emphasis on the individual: As Antonio Regalado reports here, “A person who knows He said his scientific ambitions appear to be in line with prevailing social attitudes in China, including the idea that the larger communal good transcends individual ethics and even international guidelines.” Indeed, He commissioned an opinion poll that found majority support of the Chinese public for therapeutic genetic modification (this is inline with polls in the US).

I think we will see public acceptance of genetic modification of embryos, first in the therapeutic setting, and probably first in a country such as China. As we have learnt time and again from the Assisted Reproductive Technologies space, technology does change morals.